SYMPOSIUM ON METHOXYFLURANE* FF_~ANDO HUDON, ~.D., F.la.C.P.(C), ANDm~IJACQUES,M.D., r.n.c.r.(c), MAI~CEL CLAVET, M.D., JEAN-JACQUES HOUDE, M.D,, JACQUES PELLETIER, M.D., AND MAURICE TRAdAN, ~.t,D.~ GENERAL Tr~ HALOC.ENS, particularly fluorine, are playin.g an increasing role ha medicine. Fluorine is a normal constituent of the body, beipg found especially in the bones, the hair, and the skin. It enters into the shem~caI composition of the synthetic gluco-corticoid dexamethazone (Decadron); it is also present in certain synthetic tranquilizers derived from phenothiazine: Vesprln, Perraitil, Stelazine. Fluorine is the most active and ]ightest of the halogens an~ is also the most eleetronegative. This electronegativitv is the basis of the combination of diethyl ether and halo- thane in the folznation of the azeotrope. There is also a fluorinated methane, Freoaa, which is used in industry as a refrigerant. Halothane, CF3-CHC1Br, is a fluori aated ethane used in anaesthesia. There are three other fluorinated ethanes, C FC12.CFC12, ~CF~C1.CHC12, and CF.,CI.CHCIF, which are not suitable for use as anaesthetics since they cause excitation, convulsions, and serious hypotension. They block transmission through autonomic ganglia and cause cardiac arrhythmi ~s. The fluorination of ethers has given rise to a compound which can cause exeits}tion and trembling, CFHC1CF2-- O-CH3, and two other compounds of which the therapeutic dose closely approaches the fatal dose, CFHC1CF.,-O~CH2CH~ and CFHC1CF~2-O-- CH(CH:~)._,. A fourth fluorinated ether is represented by methoxyflurane or Pen- thrane, CHC12CF2-O--CH3. It is 2,2-dichloro-l,l-difluoroethyl methyl ether, of which the structural formula is: c1 F H I I f H--C--C--O--C--H CI F H It is a clear, colourless liquid, with a characteristic fruity odour. Its boiling point is 104.65 ~ C. (220.37 ~ F. ) at atmospheric pressure (760 ram. Hg), and its freezing point is -35 ~ C. (--31 ~ F. ). 'The density or specific gravity is 1.4224 at 25 ~ IC. (77 ~ F.). Penthrane is stable in the presence of alkalis. It may therefore be used with soda lime in a closed circuit. It is stable on exposureto the air, to light, and|to humidity. *Presented at the Canadian Anaesthetists" Society, Quebec Division meeting, at the Faculty of Medicine, Laval University, March 10, 1962. tHStel Dieu de Quebec, Quebec, Canad,a. 276 Can. Anaes. Soc. J., vol. 10, no. 3, May, 1963 I-IUDON et al.: SY~$POSIUI~[ ON AIETHOXYFLU1AANE 277 Laqmd . Penthrane discolours if it is stored in contact with.I co~)per, brass, O r bronze With these metals and with aluminuln, it gives a pllecipitiate. Penthrane vapour does not cause these reactions; however, it attacks and penetratesJ n~bber but not ny]on. Study qf the physical constants Ofo methoxyflurane reveals Ithe fQllowing: Pttrity ( vapour-phase chromatography ) : 99.9 per cent Flash point (Cleveland open cup): 62 8• ~ C. (145+-5 ~ F.) Oil solubility (liquid/liquid) : miscible in all proportions \Vater solubility (polarographic titration) : 2.2 gm./litre Vaponr density (absolute) at 37 ~ C. (98.6 ~ F.): 7.36 gm./litre Absolute viscosity at 200 C. ( 68 ~ F. ) : 1.056 centipoises Absolute viscosity at 50 ~ C. ( 122 ~ F. ) : 0.690 centipoise Surface tension at 20 ~ C. (68 ~ F. ): 25.98 dynes/cm. Surface tension at 50 ~ C. ( 122 ~ F. ) : 22.45 dynes/cm. Latent heat of vaporization: 49 cal./gin. The vapour density establishes ~ 1 c.c. of methoxyflurane glve~ rise to 193 c.c. of vapour. One cubic centimetre of diethyl ether gives 220 c.c. Of vapour and 1 c c. of water gives 700 c.c. of vapour. It takes 49 calories to change 1 gin. of methoxyflurane liquid iOto vapour with- out change os temperature. For water, 580 calories are required[and for diethyI ether, 87 calories. Methoxyflurane vaporizes 12 times faster t~aan water even though their vapour pressures and boiling points are similar, anc~ this fact is due to the latent heat of vaporization of methoxyflurane. Methoxyflnrane is compatible chemically and physiologically ~r drugs com- monly used in medicine and surgery. However, it potentiates Ar~onad (trimetha- phan ~camphorsulphonate) and non-depolarizing relaxants. The relaxant action of methoxyflurane does not occur at the same level as that of d-tt~bocurarine or of gallamine and does not appear at the same stage of anaesthesia as that produced bv diethyl ether. Nonetheless, this relaxation is not dependent tIpon the appear- ance of apnoea. The use of epinephrine during methoxyflurane aUaesthesia should be approached with caution but perhaps to a lesser extent than during anaesthesia with halothane. Metl~oxyflurane is a complete inhalation anaesthetic. Its in~ravenous use is presently under study. It wdl produce surgical anaesthesia without the need for any supplementation, and produces a state of analgesia whichI lasts for a long time fol]owing awakening. The production of rapid analgesia, r~pid amnesia, and rapid relaxation are three of its characteristics. With increasing depth of anaes- thesia, respiration and circulation are comparably depressed. As wit'h all other fluorinated anaesthetics, it is necessary to assist respiration either manually or mechanically. It does not stimulate salivary or tracheobronchial secretions and does not increase pulmonary resistance. Walker, Eggers, and Allen have studied the cardiovascular~ffects of methoxyflurane compared with those of halothane in man: (a) The cardiac index (lltres/minutes/m.3) is depressed by 9.8~per cent by methoxyflurane and by 11.6 per cent by halothane. 278 CANADIAN ANAESTHETISTSi SOCIETY JOURNAL (b) The vascular resistance is diminishe d by ~1 per ~ by methoxyflurane and by 16.6 per cent by halothane. (c) The mean arterial pressure is lowere~ by 1~.9 per cent by methoxyflurane and by 24.4 per cent by halothane. (d) The pulse rate is increased by 9.5 pel- centj by methoxyflurane and dimin- ished by 4.4 per cent by halothane. These data indicate that methoxyflurane h~s Ies~ direbt depressant effect on the myocardiurn than halothane in patients withlsimilgr levels of surgical anaesthesia. Liver function tests show no greater variati'onlthan Is produced by anaesthesia with ether or with cyclopropane. Methoxyflurane ~aises the blood sugar, as does ether. Blood studies show no interference wi~h the coagulation mechanism, and methoxyflurane does not increase capillary bleeding. Studies of the distribution and excretion ofmethoxyflurane show that this anaesthetic has a predilection for the adrenal cortex, the liver, the bile, and fatty tissues, where it is stored before being eliminate~ by the lungs. This storage in fatty tissues is perhaps an explanation for the persistent postoperative analgesia which follows methoxyflurane anaesthesia. INDUCTION OF ANAESTHESIA WITH METHOXYFLURANE Induction of anaesthesia with methoxyflurane i t possible wiHa procedures simi- lar to those used with other volatile anaesthetics: It is therefore equally possible with open or semi-open systems, open drop, or by closed or semi-dosed circuit. The open or semi-open circuit or open-drop metgods are particularly applicable to children. The technique is the same as with opela-drop ether. However, since methoxytturane is much more potent, less is used, only two or three drops being given at a time. Iaduction is ~moot]~ without irritation to the respiratory passages and without excessive salivation. The fruity odour is not unpleasant and children accept it readily enough. Generally, the excitation stage is absent or slight and nausea or vomiting is rare.lHowever there is slight respira- tory depression, varying with the depth of anaesthesia. For this reason, oxygen should be given under the mask as soon as consqiousness is lost. The Guedel eye signs do not apply in methoxvflurane anaesthesia and the most reliable guides are the respiration and the arterial pressure. During incluction, the pupils remain small, the eyes becoming central and fixed as soon as the child ceases to respond to verbal command. The depth of respiration grOdually diminishes; arterial pres- sure remains constant or tends to fall a little, proportionate to the depth of anaes- thesia. With induction by the open-drop method, anaesthesia is established in two or three minutes. Methox,yflurane by the open-drop method compares very favourably with ether. Induction by methoxyflurane in semi-closed circuit is easy to produce in the adult. In the anaesthesia service at l'H6tel-Dieu de Qu6bec, different vaporizers have been used including the Heidbrink No. 8, the Vernitro], the Azeotee, antl the Fluotec in combination with Boyle's closed-circuit bottle. It has been found best to use nitrous oxide as well as oxygen during induction. For induction, Ia methoxyflurane concentration of from 0.8 to 3 per cent is necessary. HUDON et al.: SYMPOSIUlV[ ON METHOXYFLURANE 9.79 Using the Heidbrink No. 8 vaporizer, 2 litres of oxyge~ andlg, litres of nitrous oxide are given and methoxyflurane graduall); introduced Istarting at setting No. 1 and increasing fairly rapidly until the full-on position at setting JNo. 10 is reached. Here again, induction proceeds smoothly without nause~ or ~.omiting and with little or no excitatory stage. The pupils remain small duting the induction stage and the ,eye~ remain central following loss of consciou~'ness./Arterial pressure stayg normal or decreases slightly. The respiration is depresse d proporti6nate to the increasing depth of anaesthesia and for this reason it is l~referable to assist respiration when the stage of surgical anaesthesia begins. Induction takes from 5 to 10 minutes with the Heidbrinl~ No.. 8 vaporizer, v~hich is the most rapid and potent of vaporizers. With the Vernitrol ether vaporizer calibrated at I litre/minpte, induction will take a little longer and varies between 10 and 15 minutes.